Circulating pyruvate is a potent prognostic marker for critical COVID-19 outcomes

Identifier:  imarina:9282766

Handle: https://hdl.handle.net/20.500.11797/imarina9282766

Authors:  Ceperuelo-Mallafre, Victoria; Reverte, Laia; Peraire, Joaquim; Madeira, Ana; Maymo-Masip, Elsa; Lopez-Dupla, Miguel; Gutierrez-Valencia, Alicia; Ruiz-Mateos, Ezequiel; Buzon, Maria Jose; Jorba, Rosa; Vendrell, Joan; Auguet, Teresa; Olona, Montserrat; Vidal, Francesc; Rull, Anna; Fernandez-Veledo, Sonia

Abstract:
BackgroundCoronavirus-19 (COVID-19) disease is driven by an unchecked immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which alters host mitochondrial-associated mechanisms. Compromised mitochondrial health results in abnormal reprogramming of glucose metabolism, which can disrupt extracellular signalling. We hypothesized that examining mitochondrial energy-related signalling metabolites implicated in host immune response to SARS-CoV-2 infection would provide potential biomarkers for predicting the risk of severe COVID-19 illness. MethodsWe used a semi-targeted serum metabolomics approach in 273 patients with different severity grades of COVID-19 recruited at the acute phase of the infection to determine the relative abundance of tricarboxylic acid (Krebs) cycle-related metabolites with known extracellular signaling properties (pyruvate, lactate, succinate and alpha-ketoglutarate). Abundance levels of energy-related metabolites were evaluated in a validation cohort (n=398) using quantitative fluorimetric assays. ResultsIncreased levels of four energy-related metabolites (pyruvate, lactate, a-ketoglutarate and succinate) were found in critically ill COVID-19 patients using semi-targeted and targeted approaches (p<0.05). The combined strategy proposed herein enabled us to establish that circulating pyruvate levels (p<0.001) together with body mass index (p=0.025), C-reactive protein (p=0.039), D-Dimer (p<0.001) and creatinine (p=0.043) levels, are independent predictors of critical COVID-19. Furthermore, classification and regression tree (CART) analysis provided a cut-off value of pyruvate in serum (24.54 mu M; p<0.001) as an early criterion to accurately classify patients with critical outcomes. ConclusionOur findings support the link between COVID-19 pathogenesis and immunometabolic dysregulation, and show that fluorometric quantification of circulating pyruvate is a cost-effective clinical decision support tool to improve patient stratification and prognosis prediction.